rs1065852

Variant names:

• chr22-42130692-G-A
• rs1065852
• NM_000106.6:c.100C>T
• CYP2D6 p.Pro34Ser

Your query was ambiguous. Multiple possible variants found:

• chr22-42130692-G-A
• chr22-42130692-G-C

Germline classificationCancer classification (beta)

Variant summary

Our verdict is

Benign

<-10 Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

. The variant received -11 ACMG points: 1P and 12B. BA1PP3BP6_Strong

The NM_000106.6(CYP2D6):c.100C>T (p.Pro34Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a cumulative frequency of 0.212 (AC=340,585) in the gnomAD database across 1,605,342 control chromosomes, including 48,398 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.525. In-silico predictor (REVEL) classifies this variant as likely damaging/oncogenic. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. The affected nucleotide is highly conserved across species (PhyloP 100-way vertebrate score: 7.37). Variant has been reported in ClinVar as Benign/Likely Benign (★★). This exact variant is curated in the UniProt human variants database as Uncertain Significance; it is also listed as a COSMIC curated somatic variant.

• Frequency:
  • Genomes: 𝑓 0.19 (4032 hom., cov: 31)
  • Exomes 𝑓: 0.21 (44366 hom.)
• Consequence: CYP2D6 NM_000106.6 missense
• Clinical Significance: Likely benign; drug response; other criteria provided, multiple submitters, no conflicts B:1 O:5
• Conservation: PhyloP100: 7.37
• Publications: 656 publications found

Genes affected

CYP2D6 (HGNC:2625): (cytochrome P450 family 2 subfamily D member 6) This gene encodes a member of the cytochrome P450 superfamily of enzymes. The cytochrome P450 proteins are monooxygenases which catalyze many reactions involved in drug metabolism and synthesis of cholesterol, steroids and other lipids. This protein localizes to the endoplasmic reticulum and is known to metabolize as many as 25% of commonly prescribed drugs. Its substrates include antidepressants, antipsychotics, analgesics and antitussives, beta adrenergic blocking agents, antiarrythmics and antiemetics. The gene is highly polymorphic in the human population; certain alleles result in the poor metabolizer phenotype, characterized by a decreased ability to metabolize the enzyme's substrates. Some individuals with the poor metabolizer phenotype have no functional protein since they carry 2 null alleles whereas in other individuals the gene is absent. This gene can vary in copy number and individuals with the ultrarapid metabolizer phenotype can have 3 or more active copies of the gene. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2014]

NDUFA6-DT (HGNC:45273): (NDUFA6 divergent transcript)

Classification according to ACMG Germline Pathogenicity v2019

Our verdict: Benign. The variant received -11 ACMG points.

• PP3: Germline meta computational scorer (REVEL/MetaRNN/BayesDel) predicts damaging effect — supporting evidence (PP3); Splicing verdict: not pathogenic.; Germline computational verdict: pathogenic (Supporting).
• BP6: ClinVar 2-star benign — strong (BP6); ClinVar germline classification: Benign/Likely Benign, 2 star(s).
• BA1: GnomAD effective popmax AF >5% — BA1 stand-alone benign; GnomAD reliable popmax AF = 0.5246 — exceeds 5%% threshold (BA1 applied)

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000106.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP2D6	NM_000106.6	MANE Select	c.100C>T	p.Pro34Ser	missense	Exon 1 of 9	NP_000097.3
	CYP2D6	NM_001025161.3		c.100C>T	p.Pro34Ser	missense	Exon 1 of 8	NP_001020332.2	P10635-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP2D6	ENST00000645361.2	MANE Select	c.100C>T	p.Pro34Ser	missense	Exon 1 of 9	ENSP00000496150.1	P10635-1
	CYP2D6	ENST00000359033.4	TSL:1	c.100C>T	p.Pro34Ser	missense	Exon 1 of 8	ENSP00000351927.4	P10635-2
	CYP2D6	ENST00000360124.10	TSL:1	n.100C>T		non_coding_transcript_exon	Exon 1 of 8	ENSP00000353241.6	H7BY38

Frequencies

GnomAD3 genomes AF: 0.191 AC: 28692 AN: 150496 Hom.: 4035 Cov.: 31

Gnomad AFR AF: 0.125

Gnomad AMI AF: 0.301

Gnomad AMR AF: 0.153

Gnomad ASJ AF: 0.246

Gnomad EAS AF: 0.541

Gnomad SAS AF: 0.168

Gnomad FIN AF: 0.113

Gnomad MID AF: 0.114

Gnomad NFE AF: 0.223

Gnomad OTH AF: 0.177

GnomAD2 exomes AF: 0.209 AC: 50363 AN: 241260 AF XY: 0.207

Gnomad AFR exome AF: 0.123

Gnomad AMR exome AF: 0.123

Gnomad ASJ exome AF: 0.242

Gnomad EAS exome AF: 0.577

Gnomad FIN exome AF: 0.114

Gnomad NFE exome AF: 0.217

Gnomad OTH exome AF: 0.199

GnomAD4 exome AF: 0.214 AC: 311907 AN: 1454734 Hom.: 44366 Cov.: 35 AF XY: 0.213 AC XY: 153913 AN XY: 723174

African (AFR) AF: 0.121 AC: 4013 AN: 33268

American (AMR) AF: 0.126 AC: 5551 AN: 44140

Ashkenazi Jewish (ASJ) AF: 0.245 AC: 6380 AN: 26062

East Asian (EAS) AF: 0.481 AC: 18972 AN: 39452

South Asian (SAS) AF: 0.157 AC: 13392 AN: 85306

European-Finnish (FIN) AF: 0.119 AC: 6303 AN: 52978

Middle Eastern (MID) AF: 0.139 AC: 795 AN: 5708

European-Non Finnish (NFE) AF: 0.220 AC: 243823 AN: 1107808

Other (OTH) AF: 0.211 AC: 12678 AN: 60012

GnomAD4 genome AF: 0.190 AC: 28678 AN: 150608 Hom.: 4032 Cov.: 31 AF XY: 0.186 AC XY: 13671 AN XY: 73610

African (AFR) AF: 0.124 AC: 5060 AN: 40702

American (AMR) AF: 0.153 AC: 2318 AN: 15162

Ashkenazi Jewish (ASJ) AF: 0.246 AC: 851 AN: 3462

East Asian (EAS) AF: 0.541 AC: 2757 AN: 5092

South Asian (SAS) AF: 0.167 AC: 793 AN: 4760

European-Finnish (FIN) AF: 0.113 AC: 1192 AN: 10590

Middle Eastern (MID) AF: 0.119 AC: 35 AN: 294

European-Non Finnish (NFE) AF: 0.223 AC: 15038 AN: 67566

Other (OTH) AF: 0.175 AC: 364 AN: 2082

Alfa AF: 0.212 Hom.: 1373

Bravo AF: 0.192

Asia WGS AF: 0.287 AC: 996 AN: 3464

Local populations

ToMMo 61KJPN (+60KJPN MNV) AF: 0.394 AC: 47638 AN: 120914

Turkish Variome AF: 0.172 AC: 1055 AN: 6140 Hom.: 130

ABraOM SABE-WGS-1171 AF: 0.176 AC: 412 AN: 2342 Hom.: 56

ClinVar

ClinVar submissions

Significance: Likely benign; drug response; other

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not specified (1)
-	-	-	Debrisoquine, poor metabolism of (1)
-	-	-	Deutetrabenazine response (1)
-	-	-	not provided (1)
-	-	-	Tamoxifen response (1)
-	-	-	Tramadol response (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.76
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Pathogenic	0.15
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.075	T
Eigen	Pathogenic	0.72
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.82	T
MetaRNN	Benign	0.0022	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Pathogenic	4.1	H
PhyloP100		7.4
PrimateAI	Benign	0.41	T
PROVEAN	Pathogenic	-7.4	D
REVEL	Pathogenic	0.73
Sift	Uncertain	0.023	D
Sift4G	Uncertain	0.025	D
PromoterAI		0.0068	Neutral
Varity_R		0.55
gMVP		0.84
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs1065852;

hg19: chr22-42526694;

COSMIC: COSV62243216;

COSMIC: COSV62243216;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar